rs375101073

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

This summary comes from the ClinGen Evidence Repository: The highest population minor allele frequency of the NM_004992.4:c.1328C>T p.Ala443Val variant in gnomAD v4.1 is 0.00007 in the European (non-Finnish) population (not sufficient to meet BS1 criteria). The p.Ala443Val variant is observed in at least 2 unaffected individuals (internal data, Labcorp Genetics Inc.) (BS2). The p.Ala443Val variant is not currently published and is not present in additional databases (internal and publicly available), therefore, no additional criteria are applicable at this time. Computational prediction analysis tools are inconclusive for this variant (REVEL gives a score of 0.492). In the absence of conflicting evidence, this is sufficient evidence to classify the p.Ala443Val variant as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel (BS2) (MECP2 Specifications v3.0; curation approved on 02/28/2025). LINK:https://erepo.genome.network/evrepo/ui/classification/CA208615/MONDO:0010726/036

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000059 ( 0 hom. 19 hem. )

Consequence

MECP2
NM_001110792.2 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:3B:3

Conservation

PhyloP100: 5.49

Variant links:

Genes affected

MECP2 (HGNC:6990): (methyl-CpG binding protein 2) DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian development. Human proteins MECP2, MBD1, MBD2, MBD3, and MBD4 comprise a family of nuclear proteins related by the presence in each of a methyl-CpG binding domain (MBD). Each of these proteins, with the exception of MBD3, is capable of binding specifically to methylated DNA. MECP2, MBD1 and MBD2 can also repress transcription from methylated gene promoters. In contrast to other MBD family members, MECP2 is X-linked and subject to X inactivation. MECP2 is dispensible in stem cells, but is essential for embryonic development. MECP2 gene mutations are the cause of most cases of Rett syndrome, a progressive neurologic developmental disorder and one of the most common causes of cognitive disability in females. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Oct 2015]

MECP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MECP2	NM_001110792.2 link	c.1364C>T	p.Ala455Val	missense_variant	Exon 3 of 3	ENST00000453960.7	NP_001104262.1	P51608-2A0A140VKC4Q59FJ6
MECP2	NM_004992.4 link	c.1328C>T	p.Ala443Val	missense_variant	Exon 4 of 4	ENST00000303391.11	NP_004983.1	P51608-1D3YJ43Q59FJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MECP2	ENST00000453960.7 link	c.1364C>T	p.Ala455Val	missense_variant	Exon 3 of 3	1	NM_001110792.2	ENSP00000395535.2	P51608-2
MECP2	ENST00000303391.11 link	c.1328C>T	p.Ala443Val	missense_variant	Exon 4 of 4	1	NM_004992.4	ENSP00000301948.6	P51608-1
MECP2	ENST00000628176 link	c.*700C>T		3_prime_UTR_variant	Exon 5 of 5	3		ENSP00000486978.1	A0A0D9SFX7
MECP2	ENST00000407218.5 link	c.*700C>T		downstream_gene_variant		5		ENSP00000384865.2	B5MCB4

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111634

Hom.:

Cov.:

AF XY:

0.0000296

AC XY:

AN XY:

33782

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000377

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000545

AC:

AN:

183399

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67839

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000592

AC:

AN:

1098209

Hom.:

Cov.:

AF XY:

0.0000523

AC XY:

AN XY:

363575

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000772

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111634

Hom.:

Cov.:

AF XY:

0.0000296

AC XY:

AN XY:

33782

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000377

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 13, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Uncertain:1

May 31, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A443V variant (also known as c.1328C>T), located in coding exon 3 of the MECP2 gene, results from a C to T substitution at nucleotide position 1328. The alanine at codon 443 is replaced by valine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Jan 07, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Rett syndrome

Benign:1

Feb 28, 2025

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The highest population minor allele frequency of the NM_004992.4:c.1328C>T p.Ala443Val variant in gnomAD v4.1 is 0.00007 in the European (non-Finnish) population (not sufficient to meet BS1 criteria). The p.Ala443Val variant is observed in at least 2 unaffected individuals (internal data, Labcorp Genetics Inc.) (BS2). The p.Ala443Val variant is not currently published and is not present in additional databases (internal and publicly available), therefore, no additional criteria are applicable at this time. Computational prediction analysis tools are inconclusive for this variant (REVEL gives a score of 0.492). In the absence of conflicting evidence, this is sufficient evidence to classify the p.Ala443Val variant as likely benign based on the specifications defined by the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel (BS2) (MECP2 Specifications v3.0; curation approved on 02/28/2025). -

Severe neonatal-onset encephalopathy with microcephaly

Benign:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MECP2-related disorder

Benign:1

Jan 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Uncertain

0.092

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.44

T;.

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.89

D;D

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.25

T;T

MetaSVM

Uncertain

-0.20

MutationAssessor

Benign

0.34

N;.

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.76

N;N

REVEL

Uncertain

0.49

Sift

Benign

0.082

T;T

Sift4G

Benign

0.36

T;T

Polyphen

0.041

B;B

Vest4

0.31

MVP

1.0

ClinPred

0.21

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.5

Varity_R

0.16

gMVP

0.49

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over